The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art in the present invention.
Radiotracers of high specific activity are desirable for medical imaging with positron emission tomography (PET). 18F-labelled aromatic molecules of PET tracers can be synthesized via two common but direct pathways: electrophilic reactions (Lee E, et al (2011)Science, 334, 639-642) and nucleophilic substitution (Block D, et al (1987) Journal of Labelled Compounds and Radiopharmaceuticals, 24, 1029-1042; Guo N, et al (2008) Applied Radiation and Isotopes, 66, 1396-1402). Although direct electrophilic 18F-fluorination has been well established, this route has a number of drawbacks such as synthesis with fluorine gas, low radiochemical yield and low specific activity. As a result, development of a method with the ability to conduct 18F-fluorination of aromatic molecules through direct nucleophilic substitution is highly desirable.
The importance of fluorinated compounds in agrochemical, pharmaceutical and materials chemistry is well recognized. Furthermore, the radioisotope of fluorine (fluorine-18 (18F)) is an ideal radionuclide for use in Positron Emission Tomography (PET) due to its ideal half-life of 110 minutes, while sufficient to allow for the multi-step synthesis of complex radiotracers and short enough to be safe for in-vivo clinical use. There are two sources of 18F available, the electrophilic agent [18F]F2 (and derivatives thereof) and the nucleophilic agent [18F]fluoride. [18F]F2 is not as readily accessible and its production is carrier-added, decreasing the specific activity of resultant tracers. One of the limitations in use of [18F]-fluoride for PET imaging is that there are currently very few methods for its introduction into organic molecules, restricting the design of new radiotracers. The majority of existing methods for the incorporation of 18F proceed via nucleophilic substitution reactions. When possible, these displacement reactions are efficient, allowing for the synthesis of radiotracers in high specific activity and good radiochemical yields. However, the nature of this transformation introduces severe structural constraints in the design of the radiotracer and limits the possibility of PET probes.
A number of important radiopharmaceuticals have structures that are not readily amenable to traditional nucleophilic fluorination. In particular, the high electron density of arenes make them energetically unfavorable for nucleophilic addition of fluorine anion. Decreasing the electron density of the substrate via an oxidized intermediate can be an effective method for promoting nucleophilic fluorination of aromatic molecules. In principle, it is possible to introduce [18F]fluoride via nucleophilic substitution by activating aromatic compounds using a strong electron withdrawing group. However, the commonly used approaches for nucleophilic fluorination of aromatic molecules need multiple steps to bring activation and leaving groups and subsequent elimination of these groups after the introduction of [18F]fluoride, which are extremely time-consuming and lead to dramatic decay of the radioactivity of fluorinated compounds. Forming labile intermediates can increase the repertoire of radiochemical reactions applicable to small and electron rich molecules. There are also prior reports on the fluorination of aromatics such as benzene and catechol derivatives, utilizing acetonitrile solution of Et3N—HF as supporting electrolyte and source of fluoride.